Xiao-Li Liu

Paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 110 patients.

Objective: We aimed to investigate the clinical and genetic features of paroxysmal kinesigenic dyskinesia (PKD) in a large population and to analyze the genotype–phenotype correlation of PKD. Methods: We analyzed clinical manifestations and conducted PRRT2 screening in 110 patients with PKD. Clinical data were compared between 91 probands with and without PRRT2 mutations. Results: Among the enrolled participants (45 from 26 families, 65 sporadic cases), 8 PRRT2 mutations were detected in 20 PKD families (76.9%) and 14 sporadic cases (21.5%), accounting for 37.4% (34/91) of the study population. Five mutations (c.649dupC, c.649delC, c.487C>T, c.573dupT, c.796C>T) were already reported, while 3 mutations (c.787C>T, c.797G>A, c.931C>T) were undocumented. A patient harboring a homozygous c.931C>T mutation was shown to have inherited the mutation via uniparental disomy. Compared with non-PRRT2 mutation carriers, the PRRT2 mutation carriers were younger at onset, experienced longer attacks, and tended to present with complicated PKD, combined phenotypes of dystonia and chorea, and a positive family history. A good response was shown in 98.4% of the patients prescribed with carbamazepine. Conclusions: PRRT2 mutations are common in patients with PKD and are significantly associated with an earlier age at onset, longer duration of attacks, a complicated form of PKD, combined phenotypes of dystonia and chorea, and a tendency for a family history of PKD. A patient with uniparental disomy resulting in a homozygous c.931C>T mutation is identified in the present study. Carbamazepine is the first-choice drug for patients with PKD, but an individualized treatment regimen should be developed.

PRRT2 truncated mutations lead to nonsense-mediated mRNA decay in Paroxysmal Kinesigenic Dyskinesia

BACKGROUND AND PURPOSE Paroxysmal Kinesigenic Dyskinesia (PKD) is an episodic involuntary movement disorder characterized by recurrent and brief involuntary movements. Proline-rich transmembrane protein 2 (PRRT2) has been identified as the causative gene for PKD, Benign familial infantile convulsions (BFIC) and Infantile convulsions with choreoathetosis (ICCA). As well, PRRT2 mutations have been detected in patients with PED or PNKD. To date, most of the mutations have been found to be nonsense. METHOD We used inhibitors of nonsense-mediated mRNA decay (NMD) pathway --emetine dihydrochloride hydrate and cycloheximide and silencing regulator of nonsense transcripts 1(UPF1) with immortalized lymphoblasts to detect whether the truncated mutations lead to NMD, a type of mRNA surveillance in every eukaryotic cell proved so far and that generally degrades mRNA containing premature translation termination codons (PTCs). In addition, we transfected the SH-SY5Y cells with wild-type and mutant PRRT2 plasmids to identify the PRRT2 proteins subcellular localization. RESULTS We detected, low expression of truncated PRRT2 and was further rescued by applying the inhibitor of NMD pathway, suggesting that NMD plays an important role in the pathogenesis of PKD by haplo-insufficiency. Moreover, for the small portion of undegraded mutant PRRT2 that was translated into truncated proteins, their cellular localization changed from membrane to cytoplasm and nuclear, which might lead to a functional loss. CONCLUSION We suggest that the NMD of truncated mutation of PRRT2 and altered cellular localization of undegraded of PRRT2, might lead to PKD.

A community-based study of risk factors for probable rapid eye movement sleep behavior disorder

OBJECTIVES To cross-sectionally explore the potential risk factors for rapid eye movement (REM) sleep behavior disorder (RBD) in a community cohort in Shanghai. METHODS Based on the validated RBD screening questionnaire (RBDSQ), we identified individuals with probable RBD (pRBD) in 3635 community-dwelling residents (≥50 years old) from an urban community of Shanghai. Potential risk factors of pRBD, including age, sex, smoking, socioeconomic status, obesity, consumption of tea (surrogate for caffeine intake) and alcohol, medications and chronic disease status, were assessed via questionnaire. We used logistic regression to investigate the associations between these studied factors and pRBD after adjusting for age, sex and other studied factors. RESULTS Based on the RBDSQ score ≥5, 2.70% (3.28% in men and 2.41% in women) participants were considered as pRBD. We found that lower education, presence of head injury, atrial fibrillation, hyperlipidemia, constipation, olfactory disturbance, and imbalance, use of alcoholic beverage, selective serotonin reuptake inhibitor, and benzodiazepine were associated with higher likelihood of having pRBD (P < 0.05 for all). In contrast, male sex, use of coffee or tea, smoking and other factors were not significantly association with altered risk of having pRBD. We did not find significant interaction between sex, age and these factors, in relation to pRBD risk. CONCLUSIONS In this community-based study of older adults, we identified several potential risk factors for concurrent pRBD, including environmental factors and vascular risk factors.

Myotonia congenita: novel mutations in CLCN1 gene

Myotonia congenita belongs to the group of non-dystrophic myotonia caused by mutations of CLCN1gene, which encodes human skeletal muscle chloride channel 1. It can be inherited either in autosomal dominant (Thomsen disease) or recessive (Becker disease) forms. Here we have sequenced all 23 exons and exon-intron boundaries of the CLCN1 gene, in a panel of 5 unrelated Chinese patients with myotonia congenita (2 with dominant and 3 with recessive form). In addition, detailed clinical analysis was performed in these patients to summarize their clinical characteristics in relation to their genotypes. Mutational analyses revealed 7 different point mutations. Of these, we have found 3 novel mutations including 2 missense (R47W, V229M), one splicing (IVS19+2T>C), and 4 known mutations (Y261C,G523D, M560T, G859D). Our data expand the spectrum of CLCN1 mutations and provide insights for genotype–phenotype correlations of myotonia congenita in the Chinese population.

Methylation status of DJ-1 in leukocyte DNA of Parkinson's disease patients.

BackgroundDJ-1 has been thought as a candidate biomarker for Parkinson’s disease (PD). It was found reduced in PD brains, CSF and saliva, although there were conflicting results. How DJ-1 expression may be regulated is not clear. Recently, blood-based DNA methylation represents a highly promising biomarker for PD by regulating the causative gene expression. Thus, in this study, we try to explore whether blood-based DNA methylation of DJ-1 could be used as a biomarker to differentiate PD patients from normal control (NC), and whether DNA methylation could regulate DJ-1 expression in a SH-SY5Y cell model.MethodsForty PD patients and 40 NC were recruited in this study. DNA was extracted from peripheral blood leukocytes (PBLs). Methylation status of two CpG islands (CpG1 and CpG2) in promoter region of DJ-1 was explored by bisulfite specific PCR-based sequencing method. Methylation inhibitor 5-Aza-dC was used to treat SH-SY5Y cell line, DJ-1 level was detected in both mRNA and protein level.ResultsCpG sites in these two CpG islands (CpG1 and CpG2) of DJ-1 were unmethylated in both PD and NC group. In SH-SY5Y cell model treated by methylation inhibitor, there was no significant change of DJ-1 expression in either mRNA level or protein level.ConclusionsOur results indicated that DNA methylation inhibitor didn’t alter DJ-1 gene expression in SH-SY5Y cell model, and DNA methylation of DJ-1 promoter region in PBLs level might not be an efficient biomarker for PD patients.

Infantile spinal muscular atrophy with respiratory distress type I presenting without respiratory involvement: Novel mutations and review of the literature.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1), also known as distal spinal muscular atrophy 1 (DSMA1) or distal hereditary motor neuropathies type 6 (dHMN6), is a rare autosomal recessive motor neuron disorder that affects infants and is characterized by diaphragmatic palsy, distal muscular weakness and muscle atrophy. The disease is caused by mutations in the gene encoding immunoglobulinm-binding protein 2 (IGHMBP2). We present a female child with novel compound heterozygous mutations in IGHMBP2 gene c.344C>T (p.115T>M) and c.1737C>A (p.579F>L), displaying distal limbs weakness and atrophy without signs of diaphragmatic palsy or respiratory insufficiency. We review 20 reported SMARD1 cases that have no respiratory involvement or have late onsets. We propose that IGHMBP2 gene mutations are characterized by significant phenotypic heterogeneity. Diaphragmatic palsy and respiratory distress may be absent and SMARD1 should be considered in infantile with the onset of peripheral neuropathies.

Novel ATM mutations with ataxia-telangiectasia.

Ataxia telangiectasia is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia with onset in childhood, oculocutaneous telangiectasia, increased serum alpha-fetoprotein, immunodeficiency, chromosomal instability, and radiation hypersensitivity. Ataxia-telangiectasia mutated gene (ATM) is one of the known genes to be associated with ataxia telangiectasia. We reported the clinical and genetic findings of three early-onset Chinese patients who demonstrated ataxia, oculomotor apraxia, choreoathetosis, myoclonus and telangiectasia of eyes. Sequence analysis of ATM revealed two known nonsense mutations c.8287C>T and c.9139C>T in the siblings. Though the siblings carried the same mutations, they showed different clinical features involving strephenopodia, exotropia, torsion dystonia, myoclonus and extrapyramidal impairments. The other patient was compound heterozygotes for ATM: c.8911C>T and c.7141_7151delAATGGAAAAAT, both of which were not reported previously and not found in 200 control chromosomes. This study widens the spectrum of mutations and phenotypes in ataxia telangiectasia.

Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18

2759 Hereditary spastic paraplegia type 18 (HSP18) is a complicated form of autosomal recessive HSP characterized by progressive weakness and spasticity of the lower extremities, dysarthria, and cognitive decline.[1‐3] In the year 2011, HSP18, also known as Spastic Paraplegia 18 (SPG18), was firstly identified due to a candidate gene endoplasmic reticulum lipid raft‐associated protein 2 (ERLIN2) on chromosome 8p11.2 in one Saudis family.[1] During the past 5 years, another two families with SPG18 due to ERLIN2 mutations have been reported presenting with complicated phenotype.[2,3] Here, we reported a patient born in a nonconsanguineous family who possessed an autosomal recessive pure form of HSP owing to novel mutations in ERLIN2. Patient was characterized by late‐onset spasticity of lower extremities without significant speech involvement or cognitive disability.

Case report: A Chinese child with Andersen–Tawil syndrome due to a de novo KCNJ2 mutation

• We identified one de novo novel mutation in KCNJ2 gene in a Chinese patient with Andersen–Tawil syndrome.

Mutations of SCN4A gene cause different diseases: 2 case reports and literature review

SCN4A encodes the Nav1.4 channel and mutations in SCN4A lead to different ionic channelopathies. In this study, one sporadic individual of periodic paralysis, one paramyotonia family and 200 normal healthy controls are enrolled. Genomic DNA was extracted from peripheral blood leukocytes, followed by polymerase chain reaction and DNA sequencing of candidate genes, including SCN4A and CACNA1S. As a result, heterozygous mutations c.2024G>A (R675Q) and c.1333G>A (V445M) of gene SCN4A were identified in the hypokalemic periodic paralysis patient and the paramyotonia congenita family respectively. Both mutations were not detected in healthy controls. Compared with reported cases, patients with mutation R675Q usually do not present hypokalemic periodic paralysis but hyperkalemic or normokalemic periodic paralysis. The mutation V445M was first reported in Chinese patients with nondystrophic myotonias. In addition, we carried out literature review by summarizing clinical features of the 2 mutations and establish the genotype–phenotype correlations to provide guidance for diagnosis.